This project is designed to delineate the pathways of arachidonic acid (AA) metabolism in Kupffer cells of rats and mice in the normal and pathological state. AA metabolites, including prostaglandins (PG), leukotrienes (LT) and hydroxy acids (HETE's), have potent biological effects, especially as mediators of inflammation. Endotoxin, the active component of the cell wall of gram negative bacteria, causes PG release in macrophages. In vivo, administration of endotoxin causes hyperthermia, hypotension, decreased cardiac output, disseminated coagulation and other effects; inhibitors of AA metabolism can attenuate these effects of endotoxin. Kupffer cells, the fixed macrophages of the liver, play a major role in the uptake of either exogenously administered or endogenous (gut derived) endotoxin. One current theory of the pathogenesis of some liver diseases is that a defect in the ability of Kupffer cells to take up endotoxin results in increased endotoxin in both the liver and the systemic circulation, which is hepatotoxic. The present study is designed to assess the participation of Kupffer cell AA metabolites in the pathogenesis of endotoxin-induced liver disease. In order to characterize AA metabolism in pathological states the profile of AA metabolism in normal liver and isolated Kupffer cells must first be established. AA metabolism will be studied in the normal animal in 3 ways: Superfusion bioassay and radioimmunoassay of the effluent of isolated, perfused liver; conversion of [14C]AA to products using whole liver microsomes and Kupffer cell suspensions; basal and agonist stimulated release of AA metabolites from Kupffer cell monolayers. The release of AA metabolites from isolated perfused liver and Kupffer cell monolayers of normal animals in response to endotoxin and its active fraction lipid A will be compared to other agonists, including calcium ionophore A23187 and zymosan. AA metabolism in normal animals will be compared to that of the following experimental animals: animals in hyperphagocytic or hypophagocytic states, animals with endotoxin resistance (either genetic or induced by prior exposure to endotoxin), animals in endotoxic shock or animals with experimental models of liver disease characterized by either endotoxemia (galactosamine-induced) or by increased toxicity of exogenous endotoxin (c. parvum-induced). The results obtained from these studies should provide information on the relationship between endotoxin and Kupffer cell AA metabolism in liver disease with the possibility that modulation of their interactions can modify the course of hepatic disease.